Doxorubicin is also indicated for use as a component of adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer.

DOSAGE AND ADMINISTRATION

Care in the administration of doxorubicin will reduce the chance of perivenous
infiltration (seeWARNINGS). It may also
decrease the chance of local reactions such as urticaria and erythematous streaking.
On intravenous administration of doxorubicin, extravasation may occur with or
without an accompanying burning or stinging sensation, even if blood returns
well on aspiration of the infusion needle. If any signs or symptoms of extravasation
have occurred, the injection or infusion should be immediately terminated and
restarted in another vein. If extravasation is suspected, intermittent application
of ice to the site for 15 min. q.i.d. x 3 days may be useful. The benefit of
local administration of drugs has not been clearly established. Because of the
progressive nature of extravasation reactions, close observation and plastic
surgery consultation is recommended. Blistering, ulceration and/or persistent
pain are indications for wide excision surgery, followed by split-thickness
skin grafting.

The most commonly used dose schedule when used as a single agent is 60 to 75 mg/m2 as a single intravenous injection administered at 21-day intervals. The lower dosage should be given to patients with inadequate marrow reserves due to old age, or prior therapy, or neoplastic marrow infiltration.

Doxorubicin has been used concurrently with other approved chemotherapeutic agents. Evidence is available that in some types of neoplastic disease combination chemotherapy is superior to single agents. The benefits and risks of such therapy continue to be elucidated. When used in combination with other chemotherapy drugs, the most commonly used dosage of doxorubicin is 40 to 60 mg/m2 given as a single intravenous injection every 21 to 28 days.

In a large randomized study (NSABP B-15) of patients with early breast cancer
involving axillary lymph nodes (see CLINICAL PHARMACOLOGY, Clinical
Studies and ADVERSE REACTIONS, Adverse
Reactions in Patients with Early Breast Cancer Receiving Doxorubicin-Containing
Adjuvant Therapy), the combination dosage regimen of AC (doxorubicin 60
mg/m2 and cyclophosphamide 600 mg/m2) was administered
intravenously on day 1 of each 21-day treatment cycle. Four cycles of treatment
were administered.

Dose Modifications

Patients in the NSABP B-15 study could have dose modifications of AC to 75%
of the starting doses for neutropenic fever/infection. When necessary, the next
cycle of treatment cycle was delayed until the absolute neutrophil count (ANC)
was ≥ 1000 cells/mm3 and the platelet count was ≥ 100 000 cells/mm3 and
nonhematologic toxicities had resolved.

Reconstitution Directions

It is recommended that doxorubicin be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly® needle inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. The rate of administration is dependent on the size of the vein, and the dosage. However, the dose should be administered in not less than 3 to 5 minutes. Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid an administration. A burning or stinging sensation may be indicative of perivenous infiltration and the infusion should be immediately terminated and restarted in another vein. Perivenous infiltration may occur painlessly.

Doxorubicin should not be mixed with heparin or fluorouracil since it has been
reported that these drugs are incompatible to the extent that a precipitate
may form. Contact with alkaline solutions should be avoided since this can lead
to hydrolysis of doxorubicin. Until specific compatibility data are available,
it is not recommended that doxorubicin be mixed with other drugs.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Handling and Disposal

Procedures for proper handling and disposal of anticancer drugs should be considered.
Several guidelines on this subject have been published.1-8 There
is no general agreement that all the procedures recommended in the guidelines
are necessary or appropriate. However, given the toxic nature of this substance,
the following protective recommendations are provided:

Personnel should be trained in good technique for reconstitution and handling.

A designated area should be defined for reconstitution (preferably under
a laminar flow system). The work surface should be protected by disposable,
plastic-backed, absorbent paper.

All items used for reconstitution, administration or cleaning, including
gloves, should be placed in high-risk waste-disposal bags for high-temperature
incineration.

Spillage or leakage should be treated with dilute sodium hypochlorite (1%
available chlorine) solution, preferably by soaking, and then water.

All cleaning materials should be disposed of as indicated previously.

In case of skin contact thoroughly wash the affected area with soap and
water or sodium bicarbonate solution. However, do not abrade the skin by using
a scrub brush.

In case of contact with the eye(s), hold back the eyelid(s) and flush the
affected eye(s) with copious amounts of water for at least 15 minutes. Then
seek medical evaluation by a physician.

Always wash hands after removing gloves.

Caregivers of pediatric patients receiving doxorubicin should be counseled
to take precautions (such as wearing latex gloves) to prevent contact with the
patient's urine and other body fluids for at least 5 days after each treatment.

HOW SUPPLIED

Doxorubicin Hydrochloride for Injection, USP, a sterile red-orange lyophilized
powder for intravenous use only, is available in 10, 20 and 50 mg single dose
vials and a 150 mg multidose vial.

Store at controlled room temperature, 15º to 30ºC (59º to 86ºF). Protect from light. Retain in carton until time of use. Discard unused portion.

Reconstituted Solution Stability

After adding the diluent, the vial should be shaken and the contents allowed
to dissolve. The reconstituted solution is stable for 7 days at room temperature
and under normal room light (100 foot-candles) and 15 days under refrigeration
(2º to 8ºC). It should be protected from exposure to sunlight. Discard any unused
solution from the 10 mg, 20 mg and 50 mg single dose vials. Unused solutions
of the multiple dose vial remaining beyond the recommended storage times should
be discarded.

Doxorubicin Hydrochloride Injection, USP is a sterile parenteral, isotonic,
available in 5 mL (10 mg), 10 mL (20 mg), 25 mL (50 mg), and 37.5 mL (75 mg)
single dose vials and a 100 mL (200 mg) multidose vial. Each mL contains doxorubicin
HCI and the following inactive ingredients: sodium chloride 0.9% and water for
injection q.s. Hydrochloric acid is used to adjust the pH to a target pH of
3.0.

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs.
NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S.
Government Printing Office, Washington, DC 20402.